Mirtazapine, also known as 2-methyl-1,2,3,4,10,14b-hexahydrobenzo[c]pyrazino-(1,2-a) pyrido[3,2-f]azepine, is an antidepressant drug suitable for oral administration. Mirtazapine belongs to piperazinoazepine group of compounds and has the following chemical structure.

1-Methyl-3-phenylpiperazine is the key intermediate in the preparation of Mirtazapine. U.S. Pat. No. 4,062,848 has described the synthesis of Mirtazapine using 1-Methyl-3-phenylpiperazine as starting material. It is believed that the earliest synthesis of this key intermediate is that of Roderick et. al., J. Med. Chem. 1966, 181–185. This publication has reported the preparation of 1-Methyl-3-phenylpiperazine starting from α-bromophenylacetic acid ester and ethylenediamine resulting in the formation of 2-oxo-3-phenylpiperazine which is then subjected to lithium aluminium hydride reduction and subsequently methylated with methyl iodide and triethylamine in acetone.

The drawback of this method is the non-selective methylation at 1-position. A mixture of products like unreacted 2-phenylpiperazine, 1-methyl-2-phenylpiperazine and 1,4dimethyl-2-phenylpiperazine alongwith the desired 1-Methyl-3-phenylpiperazine is obtained. Therefore, extensive purification is required to obtain pure 1-Methyl-3-phenylpiperazine.

U.S. Pat. No. 6,495,685 has described the preparation of 1-Methyl-3-phenylpiperazine by reacting N-(2-chloroethyl)-N-methyl-β-chloro-β-phenylethylamine (the dichloride) of Formula III with ammonia.

This dichloride of Formula III has been prepared by chlorination of the corresponding diol, N-(2-hydroxyethyl)-N-methyl-β-hydroxy-β-phenylethylamine of Formula IV.

In U.S. Pat. No. 6,495,685, this diol has been obtained by reacting styrene oxide with N-methylethanolamine. However, the described preparation of diol results in the formation of substantial amount of isomeric compound of Formula V due to non-selectivity in this reaction.

The presence of isomeric diol of Formula V results in the formation of corresponding 1-methyl-2-phenylpiperazine isomer which contaminates the product and results in lower productivity.
Next, the same dichloride of Formula III has been treated with p-toluenesulfonamide in the U.S. Pat. No. 6,339,156 to obtain tosyl piperazine which is hydrolyzed to produce 1-Methyl-3-phenylpiperazine. However, preparation of dichloride and its isomeric purity has not been discussed in this US patent.
In view of the prior art described above, the present invention provides a new process for preparing highly pure 1-Methyl-3-phenylpiperazine where the formation of 2-phenylpiperazine, 1-methyl-2-phenylpiperazine isomer and 1,4-dimethyl-2-phenylpiperazine has been avoided.